This project has the ultimate goal of elucidating the genetic architecture of Chagas' disease in a population residing in rural Brazil. A leading cause of heart disease throughout Latin America, it affects between 16 and 18 million individuals. In Brazil alone, approximately 10 percent of the population is seropositive for T. cruzi, the parasitic cause of the disease, with sub-populations experiencing seropositivity rates as high as 65 percent. Given the large pool of primary hosts for this zoonotic disease, complete eradication of Chagas' disease through control of the arthropod vector is unlikely. Research with humans and animal models indicates that there is variation in susceptibility to infection, and disease outcome, and that this variation may be due to genetic factors. Thus, this form of heart disease represents a complex phenotype with potential genetic determinants to both susceptibility to infection and differential disease pathogenesis. The proposed project will test two general hypotheses: 1) that host genetic factors influence susceptibility to infection with Trypanosoma cruzi, cardiac consequences of T. cruzi infection, and immunological correlates of Chagas' disease, and 2) that individual loci have detectable effects on these Chagas' disease related traits. In the process of testing these hypotheses, we will 1) evaluate each individual's genotype for approximately 382 polymorphic short tandem repeats (STRs) spread throughout the genome in order to generate a population specific 10cM map; 2) quantify the effects of genetic and shared environmental factors on T. cruzi infection, ECG variables, and immunological correlates of Chagas' disease in the well-characterized population of Posse; and 3) utilize linkage analysis to localize the specific genes influencing susceptibility to T. cruzi infection, ECG variables, and immunological correlates by performing a genome wide scan for linkage using a multipoint variance component method that is appropriate for extended pedigrees. This study will be the first genome scan for susceptibility to Chagas' disease.